1. [14C]Metronidazole was rapidly absorbed from the gastro-intestinal tract of rats giving maximum blood levels of radioactivity, equivalent to 6-4 and 6-7 mug metronidazole per ml blood, 1 h after oral dosing. 2. There was rapid equilibration between blood and most tissues, although radioactivity was concentrated in the liver, kidney, gastro-intestinal tract and vaginal secretions. 3. The half-life of clearance of radioactivity from the majority of tissues was between 3 and 4 h, although it was longer in the skin (8 h) and gastro-intestinal tract (14 h). 4. Fourteen radioactive excretion products were detected in rat urine and all the major products were identified. These all contained a nitro group and represented 97 degrees of the total radioactivity excreted in urine. 5. Unchanged metronidazole was secreted throughout the entire length of the gastro-intestinal tract and into the vagina of rats. 6. A hypothesis has been proposed to explain the high clinical efficacy of metronidazole in treating trichomonal and amoebic infections.
Richard Caton is recognized as the discoverer of the waves of electrical potential which today form the basis of electroencephalography. He reported his finding in three communications, two in the British Medical Journal and one to the Ninth International Congress of Medicine at Washington, DC. After defending his priority in having made this discovery, he did no further work on the brain: his family and colleagues were unaware of his discovery for many years after his death. This was possible partly because of many other things that he did in his long life but also because, in his later years, he took deliberate steps to hide the fact that he had worked on the brain. The most important of these other activities was a practical study of the treatment of rheumatic heart disease. The basis of his treatment--complete rest in bed--is still in use today.
These papers describe an investigation of the antifilarial action of methylene violet and its derivatives, which culminated in a clinical trial of methylene violet. Unfortunately, no effect was produced against W. bancrofti or A. perstans in man.Methylene violet RRA (NN-dimethylphenosafranine) belongs to the phenosafranine series, and is the 3-amino-7-dimethylamino-derivative of the basic structure shown at the head of .) The compounds of the phenosafranine series are difficult to purify, so that figures obtained for their activity are only approximate, whereas those for the toxicity may be much increased by the presence of toxic impurities. Accordingly, the true toxicity of the different derivatives may be less than those recorded here, whereas the activity may be greater or less. METHODSThe drugs were obtained from several sources, especially from Professor W. Bradley to whom our thanks are due. The antifila'ial action of the compounds was tested in cotton rats infected with Litomosoides carinii as described by Sewell and Hawking (1950).Briefly, the drug was injected intraperitoneally once daily for six successive days; six days after the last dose, the rat was killed and the worms present in the pleural cavities were examined to see if they were alive or dead, attention being concentrated mostly on the female worms. The microfilariae in the blood were also examined, but no action upon them in vivo was detected. The result is expressed as the minimum effective dose (M.E.D.)i.e., the dose which cures (i.e., kills most of the worms) in more than three-quarters of the rats treated. This expression and that for the maximum tolerated dose have only an approximate value, but they are adequate for preliminary screening. The chronic toxicity of each compound was estimated by intraperitoneal injections into mice once daily for four days. It was reckoned empirically (on the basis of our previous experience) that the maximum dose (mg. per kg.) tolerated by cotton rats for six doses was 40 per cent of the dose (mg. per kg.) tolerated by mice for four doses. The result is expressed as the maximum tolerated dose (M.T.D.), i.e., the maximum dose tolerated by more than three-
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